Large bowel cancer in man is likely caused by carcinogens and co-carcinogens present in the bowel lumen. The present project is investigating the effects of such agents on adenosine 3'5' monophosphate (cAMP) and guanosine 3'5' monophosphate (cGMP) metabolism in colonic epithelium and is exploring differences in the metabolism between the rapidly proliferating deep layers versus superficial colonic mucosa. Studies to date have demonstrated that the colon carcinogens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methylnitrosourea (MNU) produce rapid increases in cGMP in full thickness scrapings of colonic mucosa, from man, rat and rabbit without concurrent acute increases in cAMP. MNNG and MNU also stimulate guanylate cyclase activity when added to homogenates of colonic mucosa, indicating that cGMp responses in intact cells reflect increased synthesis. Fatty acids and/or their oxidation products, which are found in increased concentrations in the colon of individuals on high fat diets and may thus be co-carcinogenic factors of such diets, also activate guanylate cyclase of colonic mucosa. Since activation of this enzyme in colon and other tissues is mediated by oxidative or free radical mechanisms, it may be a target for the action of numerous carcinogens in their reactive forms. This effect in turn may be a factor in the initiation of the transformation process. Studies are in progress to examine the extent to which other carcinogens or co-carcinogens influence cyclic nucleotide metabolism in colonic mucosa, the precise mechanisms by which the effects of MNNG and fatty acids on guanylate cyclase are expressed and the characteristics of basal and carcinogen responsive cyclic nucleotide metabolism in superficial versus deep colonic epithelium.